EP0876346B1 - Chinolinderivate als antimalariamittel - Google Patents

Chinolinderivate als antimalariamittel Download PDF

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Publication number
EP0876346B1
EP0876346B1 EP96938130A EP96938130A EP0876346B1 EP 0876346 B1 EP0876346 B1 EP 0876346B1 EP 96938130 A EP96938130 A EP 96938130A EP 96938130 A EP96938130 A EP 96938130A EP 0876346 B1 EP0876346 B1 EP 0876346B1
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Prior art keywords
chloro
quinolin
diamine
benzyl
cyclohexane
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EP96938130A
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English (en)
French (fr)
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EP0876346A1 (de
Inventor
Werner Hofheinz
Raffaello Masciadri
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention is concerned with quinoline derivatives, especially N 1 -aralkyl-N 2 -quinolin-4-yl-diamine derivatives of the general formula wherein
  • novel compounds have the property that they are active not only against chloroquine-sensitive, but also against chloroquine-resistant malaria pathogens. For this reason they are very well suited for the prophylaxis and treatment of malaria, especially in cases where the malaria pathogens are resistant to chloroquine.
  • Objects of the present invention are the mentioned compounds of formula I as well as their pharmaceutically usable salts thereof per se and as therapeutically active substances, the manufacture of these compounds and salts and their use for therapeutic purposes, especially for the prevention or treatment of malaria, as well as medicaments containing a compound of formula I or a salt thereof and the production of such medicaments.
  • C 1 -C 4 -alkyl used in the present description denotes straight-chain or branched saturated hydrocarbon residues such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl and the like.
  • Hydrogen signifies chorine, bromine, fluorine or iodine.
  • a in formula I signifies an aliphatic hydrocarbon chain
  • branched chains for example -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )- or -CH 2 C(CH 3 ) 2 -, are especially preferred.
  • cycloalkylene embraces preferably cyclopentyl or cyclohexyl.
  • Rings such as phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, naphthalen-1-yl, naphthalen-2-yl, furan-2-yl, furan-3-yl or quinolin-4-yl are preferred.
  • Preferred compounds of general formula I are especially those in which R 1 signifies chlorine, R 2 signifies hydrogen, p signifies 1, A signifies -CH 2 -C(CH 3 ) 2 - and B signifies phenyl which is unsubstituted, mono-substituted or di-substituted.
  • R 1 signifies chlorine
  • R 2 signifies hydrogen
  • p signifies 1 or 2
  • A signifies cyclohexane-1,2-diyl or cyclohexane-1,4-diyl
  • B signifies phenyl which is unsubstituted, mono-substituted, di-substituted or tri-substituted are also preferred.
  • novel compounds of formula I can be manufactured in accordance with the invention by
  • a Schiff's base of formula II is reduced.
  • Suitable reducing agents are complex hydrides, diborane, reactive metals or formic acid.
  • the use of complex hydrides such as sodium borohydride is especially preferred.
  • the reduction is carried out in a temperature range of 0 to 30°C, preferably at room temperature.
  • Suitable solvents are alcohols or mixtures of alcohols with chlorinated hydrocarbons. Ethanol or an ethanol-dichloromethane mixture is preferred for the reduction with sodium borohydride.
  • formic acid is used as the reducing agent, formic acid or another dilute acid can also be used as the solvent.
  • reaction of compounds of formula V with an amine of formula VI is effected in accordance with process variant c).
  • Halogen or aliphatic or aromatic sulphonyloxy groups are also suitable here as the leaving group X.
  • the reaction is conveniently effected in a temperature range between 120 and 180°C.
  • Phenol, ethoxyethanol, dimethylacetamide or 1-methyl-2-pyrrolidone is suitable as the solvent.
  • the reaction duration can vary between 2 and 28 hours.
  • reaction of aldehydes or ketones of formula VII with an amine of formula VI is effected in a manner known per se.
  • VII and VI are reacted in a solvent such as alcohol or toluene, with a water-separating agent such as e.g. molecular sieve optionally being added, and then a reducing agent such as a complex hydride, e.g. sodium borohydride, diborane or a metal, is then added thereto.
  • VII and VI can also be reacted in the presence of a reducing agent such as hydrogen and a catalyst or with formic acid.
  • the conversion into a pharmaceutically usable salt is effected by adding an acid.
  • Hydrochloric acid, methanesulphonic acid or acetic acid are especially preferred because of the physiological compatibility of the corresponding salts.
  • Especially suitable solvents are conveniently: water, methanol, ethanol, isopropanol, diethyl ether, acetone, N,N-dimethylformamide or dioxan.
  • the intermediates required for variants a)-d) of the process can be prepared according to methods known per se. Examples 118-124 describe some possibilities for the preparation of the required intermediates.
  • the Schiff's bases of general formula II are conveniently obtained by reacting a diamine of formula III with an aldehyde of the formula
  • the reaction is conveniently carried out in an inert gas atmosphere at a temperature which lies between 20°C and the boiling temperature of the solvent, for example of ethanol, toluene or dichloromethane.
  • the reaction time can be between 1 and 24 hours, conveniently between 2 and 12 hours.
  • the reaction water which is formed can be removed by water-binding agents such as a molecular sieve (preferably 4 ⁇ ), anhydrous sodium sulphate, by evaporation together with the solvent or by azeotropic distillation over a water separator.
  • N 1 -arylalkyl-N 2 -quinolin-4-yl-diamine derivatives of general formula I in accordance with the invention and their pharmaceutically usable salts have extremely valuable pharmacological properties.
  • novel compounds can also be used for the prophylaxis and cure of malaria even in those cases where the pathogen does not respond to chloroquine.
  • the activity of the novel compounds against not only chloroquine-resistant, but also chloroquine-sensitive malaria pathogens shows itself in a strong, in vitro measurable growth inhibition of various strains of the human-pathogenic Plasmodium falciparum, as set forth in Table 1 hereinafter.
  • the ratio of the growth inhibition of a strain which is especially resistant to chloroquine and of a strain which is sensitive to chloroquine gives as the "resistance index" a measurement for the absence of a cross-resistance with chloroquine. Since, for all novel compounds the resistance index lies between 0.7 and 2.5, they inhibit the growth of sensitive as well as resistant strains of the malaria pathogen equally effectively.
  • the culture medium consists of RPMI 1640 with the addition of 25 mM HEPES, 25 mM NaHCO 3 , 100 ⁇ g/ml neomycin and 105 human serum (A + ).
  • Human-A + erythrocytes are used as the Plasmodium falciparum host cells.
  • the parasites are maintained at 37°C in an atmosphere of 3% O 2 , 4% CO 2 , 93% N 2 and 95% relative humidity.
  • the preparations are dissolved in DMSO, pre-diluted in the culture medium to a suitable starting concentration and subsequently titrated-out on to microtitre plates in the 2nd stage over 6-7 steps.
  • the test plates are incubated under the conditions given above for 72 h.
  • the parasite growth in the different preparation concentrations is determined using [G- 3 H]-hypoxanthin incorporation compared to untreated control cultures on the same test plates.
  • the 50% growth inhibition (IC 50 ) is calculated according to logit regression analysis from the resulting dosage-activity curve.
  • the preparations are tested on at least one chloroquineresistant and one chloroquine-sensitive Plasmodium falciparum strain. Additional sensitive and resistant strains are included for futher characterization.
  • mice infected with malaria pathogens Plasmodium berghei .
  • Male albino mice IBM:MORO(SPF), FUELLINSDORF) weighing about 25 g are used as the test animals. They are kept in climatized rooms at 21-22°C in groups of 5 animals per cage. They receive ad libitum a diet feed with a low PABA content (NAFAG FUTTER " No. 9009 PAB-45, PABA content 45 mg/kg) and drinking water.
  • D0 the test animals are infected with Plasmodium berghei (strain ANKA).
  • heparinized blood of a donor mouse with about 30% parasitemia which is diluted with physiological saline such that it contains 10 8 parasitized erythrocytes per ml.
  • 0.2 ml of this suspension is injected intravenously (i.v.) into the mice to be treated and into the control mice.
  • untreated control animals the parasitemia normally reaches 30-40% on the third day after the infection (D+3) and the test animals die between days +5 and +7.
  • the substances to be tested are dissolved or suspended in distilled water or in a mixture of 7% Tween 80, 3% alcohol (96%) and water. Usually, 0.25 ml of this solution or suspension is administered once subcutaneously and perorally to groups of 5 test animals. Treatment is effected 24 hours after the infection. 10 control animals are treated in the same manner with solvent or suspension medium per test.
  • the ED 50 or ED 90 is determined mathematically by means of the JMP programme (nonlinear fit).
  • the ED 50 (ED 90 ) in mg/kg is that dose which after single administration reduces the average erythrocyte infection rate by 50% (90%) in comparison to the control group.
  • Example 3 96.0 8.0
  • Example 4 68.0 73.0
  • Example 5 83.0 69.0
  • Example 6 99.7 95.0
  • Example 7 96.0 54.0
  • Example 8 99.0 95.0
  • Example 9 66.0 74.0
  • Example 10 99.2 99.3
  • Example 11 99.9 99.8
  • Example 12 98.0 4.0
  • Example 13 99.9 99.9
  • Example 14 100.0 100.0
  • Example 15 600 92.0
  • Example 16 99.8 99.9
  • Example 17 32.0 87.0
  • Example 18 100.0 100.0
  • Example 19 21.0 toxic
  • Example 20 94.0 98.0
  • Example 21 99.9 100.0
  • Example 22 42.0 84.0
  • Example 23 97.0 98.0
  • Example 24 81.0 95.0
  • Example 25 99.2 99.8
  • Example 28 79.0 96.0
  • Example 29 74.0 99.0
  • Example 30 70.0 95.0
  • Example 31 39.0 98.0
  • Example 33 10.0 97.0
  • Example 40 95.0
  • Example 43 9
  • the compounds of formula I and the pharmaceutically acceptable acid addition salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions, or nasally.
  • the compounds of formula I and the pharmaceutically acceptable acid addition salts of the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • the pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • Medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their manufacture which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts thereof into a galenical administration form together with one or more therapeutically inert carriers.
  • compounds of general formula I as well as their pharmaceutically acceptable acid addition salts can be used for the treatment or prevention of malaria and, respectively, for the production of corresponding medicaments.
  • the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in a range of about 10 mg to about 2.5 g per day of a compound of general formula I or the corresponding amount of a pharmaceutically acceptable acid addition salt thereof, although the upper limit can also be exceeded when this is found to be indicated.
  • the mixture is diluted with 30 ml of 0.3N NaOH and extracted twice with 30 ml of dichloromethane each time.
  • the crude product obtained from these extracts is purified by flash chromatography on silica gel with ethyl acetate and ethyl acetate/methanol 5:1.
  • the purified product is converted into the hydrochloride with ethanolic hydrochloric acid and precipitated by dilution with 2-butanone. Yield: 260 mg (54%), m.p. >200°C (dec.).
  • the mixture is extracted firstly with 5 0.5 I portions of ethyl acetate, the pH is increased to 12 using KOH and the mixture is again extracted with 3 0.5 I portions of ethyl acetate.
  • the latter extract gives, after evaporation of the solvent, 29.9 g of a crude product which, for further purification, is chromatographed on 500 g of silica gel with a dichloromethane-methanol mixture in the ratio by volume 97:3.
  • the evaporation residue crystallizes after the addition of 0.5 I of n-hexane. It is filtered off ander suction and dried at 40°C/ 12 mbar.
  • the thus-obtained crude product (256 g) consists to 78% of trans-N-(7-chloro-quinolin-4-yl)-4-azido-cyclohexylamine (corresponding to 192 g, 53%) in addition to 18% of an elimination product and 7% of unreacted trans-N-(7-chloro-quinolin-4-yl)-4-methanesulphonyloxy-cyclohexylamine.
  • crystalline cis-N-(7-chloro-quinolin-4-yl)-cyclohexyl-1,4-diamine remains behind in a yield of 128 g and can be used without further purification. It can be recrystallized from methanol-diethyl ether (20.6 g from 32 g of crude product in 50 ml of methanol and 400 ml of diethyl ether); m.p. 139-140°C.
  • any of the compounds described in the foregoing can be formulated as the active ingredient according to methods known per se to give pharmaceutical preparations of the following composition: 1. 500 mg tablets Active ingredient 500 mg Lactose powd. 149 mg Polyvinylpyrrolidone 15 mg Dioctyl sodiumsulphosuccinate 1 mg Na carboxymethylstarch 30 mg Magnesium stearate 5 mg 700 mg 2. 50 mg tablets Active ingredient 50 mg Lactose powd. 50 mg Microcrystalline cellulose 82 mg Na carboxymethylstarch 15 mg 200 mg 3. 100 mg capsules Active ingredient 100.0 mg Lactose powd.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Claims (9)

  1. N1-Aralkyl-N2-chinolin-4-yl-diaminderivate der allgemeinen Formel
    Figure 00810001
    worin
    R1
    Halogen oder Trifluormethyl bedeutet;
    R2
    Wasserstoff, Halogen oder Trifluormethyl bedeutet;
    A
    Figure 00810002
    oder (C5-C6)-Cycloalkylen bedeutet;
    n
    1-4 bedeutet;
    R3 und R4
    jeweils unabhängig voneinander Wasserstoff oder Methyl bedeuten;
    p
    1-3 bedeutet; und
    B
    Pyridyl, Chinolyl, Furyl, Naphthyl, Benzo[1,3]dioxolyl, Phenyl oder substituiertes Phenyl bedeutet, wobei die Anzahl an Substituenten 1-3 ist und die Substituenten aus der Gruppe, bestehend aus Halogen, Hydroxy, C1-C4-Alkyl, C1-C4-Alkoxy, Trifluormethyl, Cyano, Di-C1-C4-alkylamino oder ihren N-Oxiden, Phenyloxy, Phenyl und Methylthio, ausgewählt sind,
    sowie pharmazeutisch verträgliche Salze der basischen Verbindungen der allgemeinen Formel I, mit der Ausnahme von:
    N3-(7-Chlorchinolin-4-yl)-N1-(3,4,5-trimethoxybenzyl)butan-1,3-diamin
    N4-(7-Chlorchinolin-4-yl)-N1-(benzyl)pentan-1,4-diamin und
    N4-(7-Chlorchinolin-4-yl)-N1-(3,4,5-trimethoxybenzyl)pentan-1,4-diamin.
  2. Verbindungen nach Anspruch 1, worin R1 Chlor bedeutet, R2 Wasserstoff bedeutet, p 1 oder 2 bedeutet, A -CH2C(CH3)2- bedeutet und B Phenyl, das mono-, di- oder trisubstituiert ist, bedeutet.
  3. Verbindungen
    N1-(7-Chlorchinolin-4-yl)-N2-(3-chlorbenzyl)-2-methylpropan-1,2-diamin,
    N1-(7-Chlorchinolin-4-yl)-N2-(benzyl)-2-methylpropan-1,2-diamin,
    N1-(7-Chlorchinolin-4-yl)-N2-(2-hydroxy-3-methoxy-benzyl)-2-methylpropan-1,2-diamin,
    N1-(7-Chlorchinolin-4-yl)-N2-(2-hydroxy-5-methoxy-benzyl)-2-methylpropan-1,2-diamin,
    N1-(7-Chlorchinolin-4-yl)-N2-(4-hydroxy-3-methoxy-benzyl)-2-methylpropan-1,2-diamin,
    trans-N1-(7-Chlorchinolin-4-yl)-N4-[2-(3,5-dimethoxy-phenyl)ethyl]cyclohexan-1,4-diamin,
    cis-N1-(7-Chlorchinolin-4-yl)-N4-(4-methoxybenzyl)-cyclohexan-1,4-diamin,
    trans-N1-(7-Chlorchinolin-4-yl)-N4-(4-dimethylamino-benzyl)cyclohexan-1,4-diamin und
    trans-N1-(7-Chlorchinolin-4-yl)-N4-(2,6-difluorbenzyl)cyclohexan-1,4-diamin
    nach Anspruch 1.
  4. Verbindungen nach Anspruch 1, worin R1 Chlor bedeutet, R2 Wasserstoff bedeutet, p 1 bedeutet, A Cyclohexan-1,2-diyl oder Cyclohexan-1,4-diyl bedeutet und B Phenyl, das unsubstituiert oder mono- oder disubstituiert ist, bedeutet.
  5. Verbindungen
    (1S,2S)-N1-(7-Chlorchinolin-4-yl)-N2-(benzyl)cyclo-hexan-1,2-diamin,
    (1S,2S)-N1-(7-Chlorchinolin-4-yl)-N2-(4-chlorbenzyl)-cyclohexan-1,2-diamin,
    (1S,2S)-N1-(7-Chlorchinolin-4-yl)-N2-(4-dimethylaminobenzyl)cyclohexan-1,2-diamin,
    cis-N1-(7-Chlorchinolin-4-yl)-N4-(4-dimethylaminobenzyl)cyclohexan-1,4-diamin,
    cis-N1-(7-Chlorchinolin-4-yl)-N4-(benzyl)cyclohexan-1,4-diamin,
    cis-N1-(7-Chlorchinolin-4-yl)-N4-(3-chlorbenzyl)cyclohexan-1,4-diamin,
    cis-N1-(7-Chlorchinolin-4-yl)-N4-(2-hydroxy-4-methoxybenzyl)cyclohexan-1,4-diamin,
    cis-N1-(7-Chlorchinolin-4-yl)-N4-(3,5-dimethoxybenzyl)cyclohexan-1,4-diamin,
    cis-N1-(7-Chlorchinolin-4-yl)-N4-(4-methylthiobenzyl)cyclohexan-1,4-diamin,
    cis-N1-(7-Chlorchinolin-4-yl)-N4-(4-diethylamino-benzyl)cyclohexan-1,4-diamin und
    cis-N1-(7-Chlorchinolin-4-yl)-N4-(biphenyl-4-ylmethyl)cyclohexan-1,4-diamin
    nach Ansprüchen 1 und 4.
  6. Arzneimittel zur Behandlung oder Prävention von Malaria, enthaltend eine oder mehrere Verbindung(en) nach einem der Ansprüche 1-5 und einen therapeutisch inerten Exzipienten.
  7. Verfahren zur Herstellung von Verbindungen nach einem der Ansprüche 1-5, wobei das Verfahren umfasst
    a) Reduktion einer Schiff'schen Base der allgemeinen Formel
    Figure 00840001
       worin die Substituenten die in Anspruch 1 beschriebene Bedeutung aufweisen,
    oder
    b) Umsetzung eines Amins der Formel
    Figure 00840002
       mit einer Verbindung der Formel X-(CH2)p-B    worin X eine Abgangsgruppe bedeutet und die anderen Substituenten die in Anspruch 1 beschriebene Bedeutung aufweisen,
       oder
    c) Umsetzung einer Verbindung der Formel
    Figure 00840003
    mit einem Amin der Formel H2N―(CH2)p-B    worin alle Substituenten die in Anspruch 1 beschriebene Bedeutung aufweisen,
       oder
    d) Umsetzen eines Ketons oder eines Aldehyds der Formel
    Figure 00850001
       worin Y
    Figure 00850002
    oder Oxo-(C5-C6)-cycloalkyl bedeutet
       und R1 und R2 die in Anspruch 1 angeführte Bedeutung aufweisen, mit einem Amin der Formel VI und einem Reduktionsmittel, und
    e) falls erwünscht, Umwandeln der erhaltenen Verbindung in ein pharmazeutisch verträgliches Säureadditionssalz.
  8. Verbindungen nach einem der Ansprüche 1-5 zur Verwendung als therapeutische Wirkstoffe gegen Malaria.
  9. Verwendung von Verbindungen nach einem der Ansprüche 1-5 zur Herstellung von Arzneimitteln zur Verwendung als therapeutische Wirkstoffe gegen Malaria.
EP96938130A 1995-11-16 1996-11-07 Chinolinderivate als antimalariamittel Expired - Lifetime EP0876346B1 (de)

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CH325095 1995-11-16
CH325095 1995-11-16
CH3250/95 1995-11-16
PCT/EP1996/004866 WO1997018193A1 (en) 1995-11-16 1996-11-07 Antimalarial quinolin derivatives

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EP0876346B1 true EP0876346B1 (de) 2001-07-25

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US7968539B2 (en) 2005-02-17 2011-06-28 State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Portland State University Quinoline derivatives and uses thereof

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AU779955B2 (en) 1999-07-13 2005-02-24 Alpha Research Group, Llc Compositions and methods for the treatment of Parkinson's disease
FR2807433B1 (fr) * 2000-04-06 2002-09-20 Centre Nat Rech Scient Molecules duales contenant un derives peroxydique, leur synthese et leurs applications therapeutiques
GB0112834D0 (en) 2001-05-25 2001-07-18 Smithkline Beecham Plc Medicaments
WO2003070244A1 (en) * 2002-02-22 2003-08-28 Abbott Laboratories Antagonist of melanin concentrating hormone and their uses
US6818772B2 (en) 2002-02-22 2004-11-16 Abbott Laboratories Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor
US20060014786A1 (en) * 2002-05-17 2006-01-19 Rajeev Raut Opthalmic pharmaceutical compositions and methods for treating ocular inflammation
US7084157B2 (en) * 2002-05-17 2006-08-01 Rajeev Raut Ophthalmic pharmaceutical compositions and methods for treating ocular inflammation
US7108992B2 (en) * 2002-11-27 2006-09-19 St. Jude Children's Research Hospital ATM kinase compositions and methods
US6916627B2 (en) * 2002-11-27 2005-07-12 St. Jude Children's Research Hospital ATM kinase compositions and methods
WO2007059372A2 (en) * 2005-11-09 2007-05-24 St. Jude Children's Research Hospital Use of chloroquine to treat metabolic syndrome
FR2902100A1 (fr) * 2006-06-13 2007-12-14 Sanofi Aventis Sa Molecules duales contenant un derive peroxydique, leur synthese et leurs applications en therapeutique
WO2010059633A2 (en) 2008-11-18 2010-05-27 Oregon Health & Science University Compounds for treating parasitic disease
GB201206280D0 (en) * 2012-04-10 2012-05-23 Univ Dundee Anti-malarial agents
JPWO2015133280A1 (ja) * 2014-03-03 2017-04-06 公立大学法人名古屋市立大学 抗マラリア活性化合物及び抗マラリア薬
US20230416786A1 (en) 2020-11-30 2023-12-28 Cellectis Sa Use of aminoquinoline compounds for higher gene integration
WO2022191092A1 (ja) * 2021-03-12 2022-09-15 国立大学法人東北大学 キノリン化合物、ｈｎｍｔ阻害剤、及びａｄｈｄ、ナルコレプシー又はアルツハイマーの予防・治療剤
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US7968539B2 (en) 2005-02-17 2011-06-28 State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Portland State University Quinoline derivatives and uses thereof
US8524739B2 (en) 2005-02-17 2013-09-03 State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Portland State University Quinoline derivatives and uses thereof
US9493420B2 (en) 2005-02-17 2016-11-15 Portland State University Quinoline derivatives and uses thereof

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DE69614149D1 (de) 2001-08-30
PT876346E (pt) 2002-01-30
AU7566996A (en) 1997-06-05
CA2237997A1 (en) 1997-05-22
GR3037018T3 (en) 2002-01-31
TR199800854T2 (xx) 1998-08-21
KR100263802B1 (ko) 2001-01-15
WO1997018193A1 (en) 1997-05-22
KR19990067646A (ko) 1999-08-25
JP3034609B2 (ja) 2000-04-17
BR9611727A (pt) 1999-05-25
JPH11500749A (ja) 1999-01-19
ATE203519T1 (de) 2001-08-15
ES2162110T3 (es) 2001-12-16
US5948791A (en) 1999-09-07
AU718932B2 (en) 2000-05-04
DE69614149T2 (de) 2002-03-14
CN1202155A (zh) 1998-12-16
MX9803827A (es) 1998-09-30
EP0876346A1 (de) 1998-11-11
DK0876346T3 (da) 2001-11-12
CN1166639C (zh) 2004-09-15

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